This project assembles a unique set of brain specimens to test hypotheses on the relationship of inflammation to synaptic regression and neuron death during normal aging and Alzheimer disease (AD) pathogenesis using microarray technology. Because AD risk is driven by aging, we will evaluate normal brains across the adult life span to identify aging changes in gene expression, which may trigger feedforward cascades leading to irreversible neurodegeneration. To carry out this project a consortium of neuroscientists, neuropathologists and clinicians representing 6 ADCs has been assembled. Frozen, unfixed blocks (250 mg/sample) of the entorhinal cortex/subiculum (EC), hippocampus (HPC), superior frontal gyrus (SFG), and sensory-motor cortex (SMC) will be obtained primarily from five well-established NIA ADC brain banks. The tissue blocks will derive from neuropathologically normal controls, MCI, early mild-moderate AD, and terminal moderate-severe AD (N=10/group). PD cases with dementia but without significant AD pathology (N=10/group) will serve as a disease control. Assignment of cases to groups will be based on common ADC antemortem clinical criteria and postmortem neuropathologic criteria, particularly Braak staging. The experimental groups will be matched for gender and postmortem intervals, none of which will exceed 6 hours, a period during which our preliminary studies suggest that relatively little RNA degradation occurs. Total RNA will be characterized for size distribution and analyzed by Affymetrix gene arrays. Data will be stored in a dedicated hard-drive and searched for changes in specific pathways that may be early markers for and underlying causes of AD study. This proposal will focus on two hypotheses: 1). During aging and mild pathology select genes linked to synaptic function show compensatory changes in the initial stages of cognitive decline and these decline as degeneration evolves. 2). Brain inflammation is a key triggering mechanism resulting in conversion to MCI and/or AD and that inflammatory responses follow or precede synaptic change. Once an initial primary paper is published the overall data will be made available to the field via NACC for various investigators to analyze for the testing their own hypotheses.